Nav: Home

Promising new drugs for old pathogen Mtb

March 28, 2019

Tuberculosis (TB), an ancient and notoriously difficult disease to treat, has killed millions through the course of human history; and the antibiotics that have been used to fight the disease in recent history are becoming less and less effective.

In the face of this reality, Dennis Wright, professor of medicinal chemistry in the University of Connecticut's Department of Pharmaceutical Sciences, has improved upon a new way to thwart the tricky pathogen, mycobacterium tuberculosis (Mtb). His findings are published today in Cell Press.

Though it may not be apparent in the United States, TB is the leading deadly infectious disease in the world, now surpassing HIV, says Wright. And the areas worst affected by TB are those that are becoming increasingly industrialized, including China, Russia, and India.

Current treatment protocols require the use of multiple drugs, due to the bacteria's uncanny ability to develop resistance to individual drugs. Drug-resistant strains may be on the rise, due to poor adherence to treatment protocols, says Wright.

"First-line therapy for drug-susceptible TB is by using three to four drugs in combination," he says. "The mixture is necessary because the pathogen is a master at developing drug resistance."

The treatment time is also at least six months for drug-susceptible strains; but for drug-resistant tuberculosis, it can be 18 months and often longer. Unfortunately, that means adherence to the full treatment, especially in less industrialized areas, is unlikely or impossible for many, Wright says.

A Different Way to Target the Bacteria

At UConn, Wright is taking a new approach, developing drugs that target the bacteria in different ways from previous classes of drugs. He says this approach is intended to help circumvent the pathogen's resistance to existing drugs.

In recent years, research into the disruption of the folate pathway in Mtb has been explored as a means of treating the infection. The folate pathway is essential for the production of nucleic acids, or the building blocks of DNA and RNA - the information needed for organisms to reproduce or replicate.

Since it is so important for survival, the folate pathway is also highly conserved - meaning that antifolate drugs could target bacteria, fungi, parasites, but also humans. Therefore just the right compound is needed to ensure that the pathogen, and not the host, is impacted.

"It is easy to make very potent antifolate compounds, but the challenge is in not impacting the human folate pathway," says Wright. "TB is very interesting because even though the folate pathway is highly conserved, there are a lot of differences in Mtb and human throughout the pathway, and those differences are what we are trying to target."

The promise for antifolate medications as a new class of drugs for the treatment of TB and many other diseases is great. However, there is currently only one antifolate used to treat TB, called para-aminosalicylic acid (PAS).

Wright and his team compared PAS with 60 antifolates they designed to target a very specific component of the folate pathway called dihydrofolate reductase (DHFR). A collaborator screened the compounds in cultures of Mtb, including drug-resistant strains.

"The Mtb and human DHFR enzymes differ very slightly, but in fact, that single amino acid change in the drug binding site is enough to give us selectivity," says Wright. Not only did the compounds have selectivity in inhibiting the pathogenic DHFR, but they also impacted the ease with which the drug enters the bacterium.

Wright says getting the drugs in is challenging, because TB is one of the hardest microorganisms to penetrate. "It is so drug-resistant due to the waxy outer coating, and because it can hide from the immune system."

Classical antifolates, like methotrexate, require active transport into cells; however, the compounds developed by Wright and his team enter the cell passively. Wright says the folate cycle may also play a role in the bacterium's ability to produce its protective waxy coat, meaning that it could make it easier for other drugs to get in and help clear a TB infection.

Wright says that these two findings were validation that the compounds were targeting what they had hoped to target; and overall, the researchers found their compounds to be more effective than PAS.

He is hopeful that funding agencies will be interested in this promising class of drugs. More work is needed to bring them to the market for the treatment of TB.

"As people are traveling more," he says, "I'm not sure how long TB will stay isolated."
-end-
This research was funded by NIH (AI104841 and AI111957).

University of Connecticut

Related Bacteria Articles:

How bacteria fertilize soya
Soya and clover have their very own fertiliser factories in their roots, where bacteria manufacture ammonium, which is crucial for plant growth.
Bacteria might help other bacteria to tolerate antibiotics better
A new paper by the Dynamical Systems Biology lab at UPF shows that the response by bacteria to antibiotics may depend on other species of bacteria they live with, in such a way that some bacteria may make others more tolerant to antibiotics.
Two-faced bacteria
The gut microbiome, which is a collection of numerous beneficial bacteria species, is key to our overall well-being and good health.
Microcensus in bacteria
Bacillus subtilis can determine proportions of different groups within a mixed population.
Right beneath the skin we all have the same bacteria
In the dermis skin layer, the same bacteria are found across age and gender.
Bacteria must be 'stressed out' to divide
Bacterial cell division is controlled by both enzymatic activity and mechanical forces, which work together to control its timing and location, a new study from EPFL finds.
How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.
The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?
Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.
Bacteria uses viral weapon against other bacteria
Bacterial cells use both a virus -- traditionally thought to be an enemy -- and a prehistoric viral protein to kill other bacteria that competes with it for food according to an international team of researchers who believe this has potential implications for future infectious disease treatment.
More Bacteria News and Bacteria Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Our Relationship With Water
We need water to live. But with rising seas and so many lacking clean water – water is in crisis and so are we. This hour, TED speakers explore ideas around restoring our relationship with water. Guests on the show include legal scholar Kelsey Leonard, artist LaToya Ruby Frazier, and community organizer Colette Pichon Battle.
Now Playing: Science for the People

#568 Poker Face Psychology
Anyone who's seen pop culture depictions of poker might think statistics and math is the only way to get ahead. But no, there's psychology too. Author Maria Konnikova took her Ph.D. in psychology to the poker table, and turned out to be good. So good, she went pro in poker, and learned all about her own biases on the way. We're talking about her new book "The Biggest Bluff: How I Learned to Pay Attention, Master Myself, and Win".
Now Playing: Radiolab

Uncounted
First things first: our very own Latif Nasser has an exciting new show on Netflix. He talks to Jad about the hidden forces of the world that connect us all. Then, with an eye on the upcoming election, we take a look back: at two pieces from More Perfect Season 3 about Constitutional amendments that determine who gets to vote. Former Radiolab producer Julia Longoria takes us to Washington, D.C. The capital is at the heart of our democracy, but it's not a state, and it wasn't until the 23rd Amendment that its people got the right to vote for president. But that still left DC without full representation in Congress; D.C. sends a "non-voting delegate" to the House. Julia profiles that delegate, Congresswoman Eleanor Holmes Norton, and her unique approach to fighting for power in a virtually powerless role. Second, Radiolab producer Sarah Qari looks at a current fight to lower the US voting age to 16 that harkens back to the fight for the 26th Amendment in the 1960s. Eighteen-year-olds at the time argued that if they were old enough to be drafted to fight in the War, they were old enough to have a voice in our democracy. But what about today, when even younger Americans are finding themselves at the center of national political debates? Does it mean we should lower the voting age even further? This episode was reported and produced by Julia Longoria and Sarah Qari. Check out Latif Nasser's new Netflix show Connected here. Support Radiolab today at Radiolab.org/donate.